SYSTEMS BIOLOGY OF AIRWAYS DISEASE ? PROGRAM PROJECT PROGRAM PROJECT ABSTRACT Asthma and chronic obstructive pulmonary disease (COPD), are the most common chronic diseases of the lung. Asthma affects 17 million U.S. children and adults and remains a major cause of morbidity (one-half million hospitalizations a year), and is the most common cause of school and work days lost. Fifteen million U.S. adults carry a diagnosis of COPD; it is estimated that 12 million more people have airflow obstruction but are undiagnosed. Asthma results in an estimated yearly asthma-related cost of over $12.7 billion. COPD is the third leading cause of mortality in the U.S. with an estimated annual cost of $49.9 billion. The combined health care costs for these conditions approximate $63 billion per year. Systems biology with integrative genetic, genomic and epigenomic approaches to elucidate the molecular causes of these diseases offer the promise of providing new avenues for their prediction, prevention and more effective treatment, thus, ultimately reducing health care costs. We continue to seek to find common genomic determinants for asthma and COPD relevant to human disease and assess their functional effects in human cellular models. Our research strategy is to integrate genetic data (Project 1) with transcriptomic data (Project 2) and methylation/microRNA data (Project 3) using systems genomics approaches that exploit epistatic interaction both within and between the projects and genome elements and, thus, focuses on the functionally most relevant pathways and network submodules for molecular validation and ultimate disease insights. In this effort, we leverage major advances in human genetics such as the HapMap Project, the ENCODE Project and the Human Epigenome Project that provide the basic understanding of genome complexity that informs our overall specific aims: (1) to integrate genetic (SNP), gene expression (transcript) and epigenetic (methylation) data for asthma, COPD and reduced lung function in these disorders; (2) to model the epistatic interactions within and between these genomic data sources to define critical network submodules for the overlap of asthma, COPD and reduced lung function; and (3) to functionally validate these network submodules identified in Aim 2 at the molecular level. To accomplish these aims we have assembled an accomplished group of investigators who have worked together for over 15 years and are experts in human genetics, gene expression and integrative genomics, epigenetics, systems biology, genomic statistics and bioinformatics and functional genomics. This group of investigators has published over 500 peer-reviewed original manuscripts since 2007 and 123 published scientific reports (with additional manuscripts either under development, under revision or awaiting decisions) directly related to the topic of the present application.